1. Field of the Invention
The present invention relates to novel, transient prodrug derivatives of the biologically active, phenolic dihydroxy natural sympathetic or sympathomimetic amines, and, more especially, relates to certain acyl-X-methylether latentiated forms of such amines, e.g., of the catecholethylamines.
As employed in this application, the expression "prodrug" denotes a derivative of a known and proven prior art compound, which derivative, when absorbed into the bloodstream of a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form and permits the same to attain a higher bioavailability level than that which could be obtained if the proven drug form, per se, was administered.
Furthermore, also as used in this application, the term "transient" denotes "cleavage" of the compounds of this invention in such a manner that the proven drug form is released and the remaining "cleaved" moiety is non-toxic and metabolized in such a manner that non-toxic, metabolic products are produced.
2. Description of the Prior Art
It is well known to this art that the phenolic dihydroxy natural sympathetic or sympathomimetic amines and their salts [hereinafter simply the "synpathomimetic amines"], e.g., epinephrine, norepinephrine, isoproterenol, isoetharine, protochylol, adrenalone, dihydroxyphenylaminobutanol, nordefrin, colterol, fenoterol, metaproterenol, terbutaline, carbidopa, methyldopa, etc., are useful active agents for the treatment or management of a wide variety of disease states or conditions, e.g., glaucoma, inflammation, itching, asthma, nasal congestion, allergic states, bronchospasm, cardiac dysfunction, bronchial constriction, peripheral vascular disease, shock, and the like. See generally Cutting's Handbook of Pharmacology, 41, "Sympathetic Stimulants or Adrenergic Agents", pp. 436-455, Sixth Edition (1979).
Nevertheless, it too is well known to the art that such sympathomimetic amines, and the various art-recognized therapeutically active derivatives thereof, are characterized by certain inherent disadvantages, notably serious bioavailability and physiological availability problems upon administration. Such reduced availability can be attributed in part to poor lipid solubility [by reason of the presence of the hydrophilic phenolic hydroxyl groups], and also to metabolic losses during and following conventional administration. Other disadvantages associated with the prior art compounds are instability to both air and light, and same are subject to chemical attack by many agents that are conventionally used in pharmaceutical preparations, as well as a variety of other unfavorable pharmacodynamic properties. Also, for certain applications, e.g., to elicit a topical anti-inflammatory response, relatively high concentrations of drug are required.
Thus, there exists a clear and present need for novel latentiated forms of the sympathomimetic amines, which derivatives would be conspicuously devoid of those disadvantages and drawbacks that to date have characterized the prior art compounds.